Antiviral Drugs I Flashcards
Why are there so few antivirals?
Most things that will kill a virus kill host cells
Two ways to interfere with virus specific function
Interfere with function unique to virus
Host function is much less susceptible
Viral specific enzyme examples?
Proteases mRNA capping enzyme Neuraminidase Ribonucleases Kinases Integrases Uncoating Enzymes
Effective antivirals have a therapeutic index of…
100 to 1000
T or F. Antiviral resistance is rare.
False
Becoming more and more common
Chronic viral infections are caused by…
ability of the virus to become latent
Stages of viral replication targeted for therapy
Prevention of entry into host cells Inhibition of uncoating Integrase Inhibitors Duplication of genome Transcription Translation and Post-Translational modification Assembly
Three envisioned subclasses of drugs that prevent viral entry into cells
- Inhibitors that compete to attach at viral receptor
- Coreceptor Agonists
- Fusion Inhibitors that prevent fusion
Why haven’t drugs that prevent viral entry into host cells ebcome a common thing?
Unstable peptides that mimic the receptor
Name the coreceptor antagonist drug in the works for AIDS treatment
Maraviroc
How can HIV-1 resist Maraviroc?
Using the drug bound CCR5 as a coreceptor
Noncompetitive Resistance
Is Maraviroc intended for treatment naive or treatment experienced patients?
Effective for both
Maraviroc dosing should be adjusted if…
used with drugs that inhibit or stimulate CYPA3
What is Enfuvirtide?
A fusion inhibitor for combination therapy in individuals not responding to current HIV regimens.
Derived from gp41 sequenc
Downside of enfuvirtide?
Low oral bioavailability
Virus uncoating corresponds to…
Loss of viral protein coat
Fusion of viral lipid membranes
Trigger for viral uncoating?
Low pH at the level of the endosomes or lysosomes
fusion with the plasma membrane doesn’t require a pH change
Important viral uncoating drugs
Amantidine, Rimantidine
What do you call a drug developed to prevent the insertion of the viral genetic code?
INSTIs - Integrase Strand Transfer Inhibitors
Used in AIDS treatment
First approved integrase inhibitor?
Raltegravir
Example of a second generation integrase inhibitor?
Why is it better?
Dolutegravir
Limited Cross Resistance Profile
Antiviral drugs that act on polymerases are usually…
Nucleoside analogs containing altered sugars/bases
Which class of antivirals is the best? Why?
Drugs that inhibit viral genome duplication
- Drug may be activated by virus specific enzymes
- Viral polymerases are much more sensitive than host enzymes
One enzyme commonly used to activate antiviral medications with DNA synthesis is…
Thymidine Kinase
ex. herpes simplex
Why would a virus need to bring its own kinase (like thymidine kinase)?
To allow replication in non-replicating cells (like herpes in neurons)
Why aren’t thymidine kinase drugs active against healthy cells?
Thymidine kinase is has much less specificity for what nucleotides it will accept
How do drugs use thymidine kinase to attack virus infected cells?
Nucleoside analog admitted
Phos. by thymidine kinase into triphosphate compound
Incorporated into growing nucleic acid chain
Irreversible association with viral polymerase
Termination
Important examples of drugs that inhibit duplication of the viral genome?
idoxuridine
Ribaviron
Acyclovir
Gancyclovir
Ways that drugs may target mRNA transcription and processing?
Target polyadenylation, methylation, capping, and splicing of Viral RNA
Important antivirals that inhiit mRNA transcription and processing.
Ribaviron
Interferon
Ribozymes (ex. RNA molecules that induce specific clevage of Nucleic Acids)
Specific inhibitors of viral protein translation
They are a myth.
The don’t exist.
Let it go.
Nonspecific inhibitors of viral protein translation
Interferon
Post-translational modifications of proteins targeted by anti-virals
Glycosylation (fingers crossed)
Phosphorylation (no good drugs yet…)
Fatty acetylation (in the works…)
*Sialidation (Sialidase = Neurominidase)
Significance of neuraminidase?
Spreads flu from cell to cell by removing sialic acid from the surface, allowing viral particles out
Potent inhibitor of viral neuraminidase for Influenza A and B
Zanamivir
Suspected mechanism for Nitazoxanide
Might block glycosylation of hemagluttinin in the golgi
Prevents the molecule from getting to the surface
Can’t get into viral particle
Drugs that inhibit assembly of molecular components into the whole virus
Ex. Protease Inhibitors in HIV (aquinavir, ritonavir, indinavir)
Amantadine is used to treat…
Influenza A (not B)
Amantadine works by…
- inhibiting the uncoating of the viral RNA of Influenza A
2. Influences maturation of HA glycoprotein
Amantadine is lysosomotropic. So what?
This allows it to act on the maturation stage of the virus in the trans-golgi network. It can inhibit acidification.
Absorption and elimination of Amantadine?
Well absorbed orally
Eliminated unchanged in urine
Uses of Amantadine?
Oral prophylaxis against Inf. A
Side effects of Amantadine?
GI Intolerance and CNS complaints
Who has greater activity, Amantadine or Rimantidine
Rimantidine
First generaltion polymerase inhibitor
and actually first antiviral drug
Idoxuridine
How does idoxuridine work?
It is a pyrimidine analog that inhibits viral DNA synthesis after activation by phosphorylation by thymidine kinase
Idoxuridine is primarily active against…
Used for – epithelial herpetic keratiits
Active against - Herpes, Pox viruses
Why is Idoxuridine toxic?
It lacks specificity – also hits the host DNA polymerase
Important druf related to Idoxuridine?
Trifluridine – a fluorinated Idoxuridine
use of Trifluridine?
Topical herpes keratitis treatment
Primary keratoconjunctavitis
What are cytarabine and vidarabine?
Nucleoside analogs of cytosine and adenine
Activated by Phosphorylation
List of main drugs acting against DNA/RNA polymerase activity
Idoxuridine Cytarabine and vidarabine ribavirin acyclovir gancyclovir Azidothymidine
What is Ribavirin?
A triazole purine nucleoside that inhibits repication of RNA/DNA viruses in vitro
Notably acts as a guanosine analog and inhibits 5’ cap on mRNA
Ribavirin is used to treat?
*RSV
*Parainfuenza
Lassa Fever+Other Hemorrhagic fevers
Hep C
Problem with ribavirin
Toxicity is high
Dose dependent hemolytic anemia
Mutagenic+Teratogenic
What does Acyclovir do?
Easily activated by herpes thymidine kinase
Acyc. –> Acyclovir monophosphate
Acyclovir is a purine analog that competes with dGTP
Incorporation, DNA synth. blocking by blocking DNA polymerase
Triphosphate also acts as a chain terminator
Side effects of Acyclovir
Nausea and Diarrhea
Tissue Irritation
Use acyclovir for…
Herpes, Varicella,
EBV, CMV
How is gancyclovir different from acyclovir?
Phosphation can occur from cellular enzymes
Higher risk of toxicity
gancyclovir mode of administration.
Orally, IV, or intraocular
Who do you use gancyclovir on?
Life or sight threatening CMV in immunocompromised hosts
Azidothymidine/Zidovudine mechanism of action
Chain terminator
P’d by cell kinase
Reverse transcriptase is (more or less) sensitive to Azidothymidine/Zidovudine than DNA-dependent?
More
How is Azidothymidine/Zidovudine administered?
per os
Wide distribution in body
Drugs that can enhance Azidothymidine/Zidovudine activity?
Acyclovir
Interferon
Side effects of Azidothymidine/Zidovudine?
Granulocytopenia and Anemia
GI probs, Paresthesia, rash, liver probs, myopathy
Increased risk of side effects if Azidothymidine/Zidovudine is taken with what drugs?
Ones that interact with the glucuronyl transferase pathway (aspirin, Tylenol)
Azidothymidine/Zidovudine s typically used in treatment of…
HIV (w/ lamivudine)
Lamivudine is very efficient against…
If resistance to Lam., use….
Hep B
Adefovir, an analog of adenosine monophosphate
List three important nucleoside reverse tanscriptase inhibitors
Zidovudine, Lamivudine, Tenofovir
The only nucleotide reverse transcriptase inhibitors
Tenofovir, Sofosbuvir
